An extraordinarily high incidence rate of amyotrophic lateral sclerosis (ALS) and Parkinson's Dementia Complex (PDC) was documented in the 1950's among Chamorros living on Guam. ALS has declined markedly on Guam over the following 50 years but PDC has declined to a lesser degree. Among older Chamorros, late-life dementia clinically resembling Alzheimer's disease (AD) is now at least as common as PDC. We aim to carry out a population-based study to characterize the rates of dementia and PDC among Chamorros on Guam. Our overall hypothesis is that interactions between genetic and environmental factors and aging explain the complex pattern of neurodegenerative disorders seen on Guam and the rapid changes in patterns of disease. We hypothesize that the Chamorros have a genetic predisposition to form neurofibrillary tangles (NFT). When this predisposition is combined with a strong exposure to factors in the environment, ALS and PDC may result. When Chamorros escape these two disorders, factors associated with aging and the brain, particularly oxidative stress, may result in tangle formation and late-life dementia. Specific aims of project 1 of this renewal are: 1) To determine the prevalence of dementia ('pure' dementia, PDC and other causes) among Chamorros on Guam aged 65 and older; 2) To determine the age- and sex-specific incidence of dementia among Chamorros on Guam; 3) To examine the effect of putative risk factors on the prevalence and incidence of dementia and PDC. Potential risk factors include environment: (traditional Chamorro diet and lifestyle; sources of water); genetics (family history of ALS or PDC; ApoE e4 allele; tau polymorphisms and other candidate genes); risk factors for AD (education, head trauma, head circumference and others); biological measures (plasma levels of F-2-isoprostanes; cholesterol levels); 4) To characterize neuropathologic changes among elderly Chamorros who are cognitively normal and those who have clinical syndromes of dementia or AD. This project will draw on the Clinical core on Guam; Neurologists and a neuropsychologist at UCSD and OHSU; a Neuropathology core at Mt Sinai Hospital, New York, and Neuroepidemiologists at University of South Florida. The project is planned for 5 years.